USPTO Patents Application 09993647

(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)

(19) World Intellectual Property Organization

International Bureau

(43) International Publication Date
19 March 2009 (19.03.2009)

PCT

(10) International Publication Number

WO 2009/034308 A2

(51) International Patent Classification:

C07C 233/65 (2006.01) C07C 275/64 (2006.01)
C07C 271/58 (2006.01) C07D 213/81 (2006.01)
C07C 275/30 (2006.01)

(21) International Application Number:

PCT/GB2008/003048

(22) International Filing Date:

10 September 2008 (10.09.2008)

(25) Filing Language:

(26) Publication Language:

(30) Priority Data:

1734/MUM/2007

English
English

1733/MUM/2007

10 September 2007 (10.09.2007) IN
10 September 2007 (10.09.2007) IN

(71) Applicant (for all designated States except US): CIPLA
LIMITED [IN/IN]; 289 Bellasis Road, Mumbai central,
Mumbai 400 008 (IN).

(71) Applicant (for MW only): CURTIS, Philip, Anthony

[GB/GB] ; A A Thornton & Co, 235 High Holborn, London
WC1V 7LE (GB).

(72) Inventors; and

(75) Inventors/Applicants (for US only): RAO, Dharmaraj,
Ramachandra [IN/IN]; 4/403 Garden Enclave, Pokhran
Road 2, Thane (West), Mumbai 400 601, Maharashtra (IN).
KANKAN, Rajendra, Narayanrao [IN/IN]; 1204, Her-
itage, Hiranandani Gardens, Powai, Mumbai -400 076 (IN).

GHAGARE, Maruti [IN/IN]; 204/4 Shree Swamikrupa,
Dhokali, Kolshet Road, Thane (West) 400 607, Maharash-
tra (IN). CHIKHALIKAR, Sandip [IN/IN]; A-16, 3rd
Floor, Sampada, CHS, Telli-Galli Cross Lane, S.N. Marg
S.N. Nagar, Andheri (East), Mumbai 400 069 (IN).

(74) Agents: COTTRILL, Emily, Elizabeth, Helen et al.;
A.A. THORNTON & CO, 235 High Holborn, London
WC1V 7LE (GB).

(81) Designated States (unless otherwise indicated, for every
kind of national protection available): AE, AG, AL, AM,
AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA,

CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE,
EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID,
IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK,
LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW,
MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT,
RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TJ,
TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM,
ZW

(84) Designated States (unless otherwise indicated, for every
kind of regional protection available): ARIPO (BW, GH,
GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI,
FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MT, NL,
NO, PL, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG,

CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG).

Published:

— without international search report and to be republished
upon receipt of that report

(54) Title: PROCESS FOR THE PREPARATION OF A RAF KINASE INHIBITOR AND INTERMEDIATES FOR USE IN THE
PROCESS

<

m

O

o
O

(A)

OH

(a)

(57) Abstract: There is provided a process for preparing sorafenib or a salt thereof comprising the use of a compound of formula (A),
wherein R' is selected from the group consisting of hydrogen, -C(0)OA, -C(0)CX 3 , - OH C(0)NH 2 , -C(0)-NHOH or (a). There
is also provided intermediate compounds of general formula (A), N-methyl-4-(4-ureidophenoxy)picolinamide, 4-(2- (methylcar-
bamoyl)pyridin-4-yloxy)phenylcarbamate derivative and N-methyl-4-(4-(2,2,2- trihaloacetamido)phenoxy)picolinamide, processes
for their preparation and their use in the preparation of sorafenib.

WO 2009/034308

PCT/GB2008/003048

1

PROCESS FOR THE PREPARATION OF A RAF KINASE INHIBITOR AND

INTERMEDIATES FOR USE IN THE PROCESS

5 Technical Field of the Invention

The present invention relates to a novel process for the preparation of 4-(4-{3-[4-chloro-3-
(trifluoromethyl)phenyl]ureido}^ or its

pharmaceutical^ acceptable salts.

10

Background of the Invention

4-( 4 -{3-[4-chloro-3-(M^

carboxamide is commonly known as sorafenib (I). Sorafenib is prepared as its tosylate
15 salt. Sorafenib blocks the enzyme RAF kinase, a critical component of the RAF/MEK/ERK
signaling pathway that controls cell division and proliferation; in addition, sorafenib inhibits
the VEGFR-2/PDGFR-beta signaling cascade, thereby blocking tumor angiogenesis.

Sorafenib, marketed as Nexavar by Bayer, is a drug approved for the treatment of
20 advanced renal cell carcinoma (primary kidney cancer). It has also received "Fast Track"
designation by the FDA for the treatment of advanced hepatocellular carcinoma (primary
liver cancer). It is a small molecular inhibitor of Raf kinase, PDGF (platelet-derived growth
factor), VEGF receptor 2 & 3 kinases and c Kit the receptor for Stem cell factor.

F

H H

25 (")

WO 2009/034308

PCT/GB2008/003048

2

Sorafenib and pharmaceutical^ acceptable salts thereof is disclosed in WO0042012.
Sorafenib is also disclosed in WO0041698. Both these patents disclose processes for the
5 preparation of sorafenib.

WO0042012 and WO0041698 describe the process as given in scheme I which comprises
reacting picolinic acid (II) with thionyl chloride in dimethyl formamide (DMF) to form acid
chloride salt (III). This salt is then reacted with methylamine dissolved in tetrahydrofuran
10 (THF) to give carboxamide (IV). This carboxamide when further reacted with 4-
aminophenol in anhydrous DMF and potassium tert-butoxide 4-(2-(N-methylcarbamoyl)-4-
pyridyloxy)aniline (V) is formed. Subsequent reaction of this aniline with 4-chloro-3-
(trifluoromethyl) phenyl isocyanate (VI) in methylene chloride yields sorafenib (I). The
reaction is represented by Scheme I as given below.

15

Scheme I

WO 2009/034308

PCT/GB2008/003048

N

COOH

Picolinic acid (II)

CI

SOCL

CI

DMF

CH 3 NH 2 in THF

N

COCI

4-Chloropyridine-2-carbonyl
chloride hydrochloride (III)

NCO

4-chloro-3-trifluoromethyI
phenyl isocyanate (VI)

CH 2 CI 2

N

CONHCH.

4-Chloro-N-methyl-2-
pyridine carboxamide (IV)

OH

Potassium tert
butoxide

in DMF

NK

H 2 N

4-(4-aminophenoxy)-N-
methylpicolinamide (V)

Sorafenib (I)

WO2006034796 also discloses a process for the preparation of sorafenib and its tosylate
salt. The process comprises reacting 2-picolinic acid (II) with thionyl chloride in a solvent
5 inert toward thionyl chloride without using dimethyl formamide to form acid chloride salt
(III). This acid salt on further reaction with aqueous solution methylamine or gaseous
methylamine gives compound (IV). Compound (IV) is then reacted with 4-aminophenol
with addition of a carbonate salt in the presence of a base to yield compound (V).

10 Compound (V) can also be obtained by reacting compound (IV) with 4-aminophenol in the
presence of water with addition of a phase transfer catalyst. Compound (V) when reacted
with 4-chloro-3-(trifluoromethyl) phenyl isocyanate (VI) in a non-chlorinated organic
solvent, inert towards isocyanate gives sorafenib (I). Sorafenib by admixing with p-

WO 2009/034308

PCT/GB2008/003048

4

toluenesulfonic acid in a polar solvent gives sorafenib tosylate (VII). The reaction
represented by Scheme II as given below.

Scheme II

ci

SOCL

CI

N COOH

Picolinic acid (II)

Aq. CH 3 NH 2

N

COCI

4-Chloropyridine-2-carbonyl
chloride hydrochloride (III)

CI

•a

NCO

4-chloro-3-trifluoromethyl
phenyl isocyanate (VI)

N
H

Sorafenib (I)

Polar solvent

N CONHCH3

4-Chloro-N-methyl-2-
pyridine carboxamide (IV)

OH

Potassium tert
butoxide

■CH.

CH.

N
H

Sorafenib tosylate (VII)

in DMF

4-(4-aminophenoxy)-N-
methylpicolinamide (V)

COOH

WO 2009/034308

PCT/GB2008/003048

5

A key step in the synthesis of sorafenib is the formation of the urea bond. The processes
disclosed in the prior art involve reactions of an isocyanate with an amine. These
isocyanate compounds though commercially available are very expensive. Further
synthesis of isocyanate is very difficult which requires careful and skillful handling of
5 reagents.

Isocyanate is prepared by reaction of an amine with phosgene or a phosgene equivalent,
such as bis(trichloromethyl) carbonate (triphosgene) or trichloromethyl chloroformate
(diphosgene). Isocyanate can also be prepared by using a hazardous reagent such as an
10 azide. Also, the process for preparation of an isocyanate requires harsh reaction
conditions such as strong acid, higher temperature etc. Further, this isocyanate is reacted
with an amine to give urea.

Reactions of isocyanates suffer from one or more disadvantages. For example phosgene
15 or phosgene equivalents are hazardous and dangerous to use and handle on a large
scale. These reagents are also not environment friendly. Isocyanates themselves are
thermally unstable compounds and undergo decomposition on storage and they are
incompatible with a number of organic compounds. Thus, the use of isocyanate is not well
suited for industrial scale application.

20

Hence, there is a need to develop simple and less hazardous process for large scale
production. There is also a need to avoid, as far as possible, the use of hazardous
chemicals and a need to use safer reagents which can be stored, handled without special
precaution and which are environment friendly.

25

Objects of the invention

It is an object of the present invention to provide novel key intermediates for the synthesis
of sorafenib or its pharmaceutical^ acceptable salts.

30

WO 2009/034308

PCT/GB2008/003048

6

It is another object of the present invention to provide processes for the preparation of the
novel key intermediates useful in the synthesis of sorafenib or its pharmaceutically
acceptable salts.

5 It is yet another object of this invention to provide simple and novel processes for the
preparation of sorafenib or its pharmaceutically acceptable salts using the novel key
intermediates.

Summary of the Invention

10

According to a first aspect of the present invention, there is provided a compound of
formula (A)

CI

15

wherein R' is selected from the group consisting of -C(0)OA, »C(0)CX 3 , -C(0)NH 2 ,-C(0)-
NHOH or

20

These novel compounds of formula (A) may be used in a number of novel processes for
preparing sorafenib or a salt thereof. None of the processes for preparing the compounds
of formula (A), nor any of the processes for preparing sorafenib or a salt thereof using the
compounds of formula (A), involve the use of isocyanate derivatives. As discussed above,
25 isocyanates are highly disadvantageous because they are expensive, hazardous to make

WO 2009/034308

PCT/GB2008/003048

7

and hazardous to use. The compounds of formula (A) of the present invention on the other
hand, are simple and safe to use so are much more suitable for industrial scale-up
compared to the isocyanates of the prior art. Therefore, the processes of the present
invention are highly advantageous.

5

In an embodiment, R' in compound (A) is hydrogen, and the compound of formula (A) is 4-
chloro-3-trifluoromethylaniline. In this embodiment, the compounds that are condensed
with 4-chloro-3-trifluoromethylaniline to form sorafenib (compounds (6) and (7), described
in more detail below) are novel. These intermediates are highly advantageous for the
10 same reasons as given above, i.e. they are safe and simple to use compared to
isocyanates used in the prior art.

In another embodiment, R' is , and the compound of formula (A) is

compound (1) described in more detail below.

15

In another embodiment, R' is -C(0)OA, and the compound of formula (A) is carbamate
derivative (2) described in more detail below.

In another embodiment, R' is -C(0)CX3, and the compound of formula (A) is anilide
20 derivative (3) described in more detail below.

In another embodiment, R' is -C(0)NH2, and the compound of formula (A) is urea
derivative (4) described in more detail below.

25 In another embodiment, R' is -C(0)-NHOH, and the compound of formula (A) is hydroxy
urea derivative (9) described in more detail below.

WO 2009/034308 PCT/GB2008/003048

8

According to another aspect of the present invention, there is provided a process for
preparing sorafenib or a salt thereof comprising the use of a compound of formula (A)

H (A)

5

wherein R' is selected from the group consisting of hydrogen, -C(0)OA, -C(0)CX 3 , -

C(0)NH 2 , -C(0)-NHOH or

According to another aspect of the present invention, there is provided a compound of
10 formula (1)

c 'TXa n XX (1)

H H K J

According to another aspect of the present invention, there is provided a process for
15 preparing a compound of formula (1) comprising reacting carbamate derivative (2)

(2)

WO 2009/034308

PCT/GB2008/003048

9

wherein A is alkyl or aryl, with 4-aminophenol in the presence of a solvent to obtain
carbamate derivative (2). In an embodiment, alkyl is C1-3 alkyl, suitably methyl, ethyl, iso-
propyl or n-propyl. In another embodiment, aryl is phenyl. In an embodiment, the
5 carbamate derivative may be prepared by the process described below.

The reaction of carbamate derivative (2) with 4-aminophenol may be carried out at a
temperature ranging from 0 to 60°C, preferably from 40 to 60°C.

10 The solvent may be an include organic solvent such as water, methylene dichloride
(MDC), ethylene dichloride, tetrahydrofuran (THF), 1,4-dioxane, methyl isobutyl ketone,
ethyl methyl ketone, toluene, N,N-dimethyl formamide (DMF), dimethylsulfoxide (DMSO),
ethyl acetate, acetone, acetonitrile or mixtures thereof.

15 According to another aspect of the present invention, there is provided a process for
preparing a carbamate derivative (2) comprising reacting 3-trifluoromethyl-4-chloroaniline
with a haloformate (2a) or a carbonate derivative (2b)

0 2b

CF,

1 . xSul

3- trifluorometh^- A It

4- chloro aniline o

N O

R. O H ,!

A

Carbamate derivative
(2)

20 2a

wherein in haloformate (2a), A is alkyl or aryl, and in carbonate (2b), A is alkyl, aryl or the
two A groups taken together form a 5 to 7 membered ring, in the presence of a base and a
solvent to obtain carbamate derivative (2). The carbamate derivative (2) may be used in
the process described above for preparing the compound of formula (1 ).

25

WO 2009/034308 PCT/GB2008/003048

10

In an embodiment, alkyl is C1-3 alkyl, suitably methyl, ethyl, iso-propyl or n-propyl. In
another embodiment, aryl is phenyl. The carbonate derivative may be an aliphatic
compound. Alternatively, the carbonate derivative may be a cyclic compound, i.e. the two
A groups may be joined to form a 5 to 7 membered ring. The ring members making up the
5 A group are suitably CH 2 groups. In an embodiment, the moiety of the carbonate joining
the two oxygen ring members is -CH 2 CH 2 . In an embodiment, the haloformate or
carbonate derivatives are selected from but not limited to phenyl chloroformate, methyl
chloroformate, ethyl chloroformate, diethyl carbonate and [1,3]dioxolan-2-one.

10 The base used may be an organic or inorganic base. The inorganic base may be selected
from potassium tertbutoxide, potassium hydroxide, sodium hydroxide, ammonium
hydroxide, sodium methoxide, potassium methoxide, potassium carbonate, sodium
carbonate and the like. The organic base may be selected from pyridine, dimethyl amine,
triethyl amine, N,N-diisopropylethyl amine and 1,8-diazabicyclo[5.4.0]undec-7-ene.

15

The reaction of 3-trifluoromethyl-4-chloroaniline with the haloformate or carbonate
derivative may be carried out at a temperature ranging from -10 to 25°C, preferably from -
5 to 5°C. Typically, the haloformate or carbonate derivative is added slowly so as to
maintain the desired temperature of the reaction mass during the addition of the
20 haloformate or carbonate derivative.

According to another aspect of the present invention, there is provided a process for
preparing a compound of formula (1) comprising reacting anilide derivative (3) with 4-
aminophenol

25

WO 2009/034308

PCT/GB2008/003048

11

wherein X is halogen, in a solvent to obtain compound (1). In an embodiment, the
compound of formula (3) is prepared according to the process described below.

In an embodiment, the reaction is carried out at a temperature ranging from 100 to 140°C,
5 preferably from 1 1 0 to 120°C.

The solvent may include organic solvent such as water, methylene dichloride (MDC),
ethylene dichloride, tetrahydrofuran (THF), 1,4-dioxane, methyl isobutyl ketone, ethyl
methyl ketone, toluene, N,N-dimethyl formamide (DMF), dimethylsulfoxide (DMSO), ethyl
10 acetate, acetone, acetonitrile or mixtures thereof.

According to another aspect of the present invention, there is provided a process for
preparing anilide derivative (3) comprising reacting 3-trifluoromethyl-4-chloroaniline with a
trihaloalkyl halide, a trihaloalkyl anhydride or a trihaloalkyl ester,

15

O

A.

X^ cx„

(CXBCDDfeO OR
C^COOR

CF

CI

O
U

N CX.
H •

wherein X is halogen and R is alkyl, to obtain anilide derivative (3).

20 X in trihaloalkyl halide or anhydride or ester is halogen such as chlorine, bromine or iodine,
preferably chlorine.

WO 2009/034308

PCT/GB2008/003048

V

12

In an embodiment, the trihaloalkyl halide or anhydride or ester is selected from
trichloroacetyl chloride, tribromoacetyl chloride, trichloro acid anhydride, ethyl
trichloroacetate, methyl trichloroacetate, phenyl trichloroacetate and ethyl tribromoacetate.

5 The reaction of the trihaloalkyl halide or anhydride or ester may be carried out at a
temperature ranging from -5 to 25°C. Typically, the trihaloalkyl halide or anhydride or ester
is added slowly so as to maintain the desired temperature of the reaction mass during the
addition the trihaloalkyl halide or anhydride or ester.

10 Optionally, the reaction is carried out in the presence of a base. The base used may be an
organic or inorganic base. The inorganic base may be selected from potassium
tertbutoxide, potassium hydroxide, sodium hydroxide, ammonium hydroxide, sodium
methoxide, potassium methoxide, potassium carbonate, sodium carbonate and the like.
The organic base may be selected from pyridine, dimethyl amine, triethyl amine, N,N-

15 diisopropylethyl amine and 1 ,8-diazabicyclo[5.4.0]undec-7-ene.

According to another aspect of the present invention, there is provided a process for
preparing a compound of formula (1) comprising reacting urea derivative (4) with 4-
aminophenol in a solvent to obtain compound (1).

20

Urea derivative (4)

In an embodiment, the urea derivative (4) is prepared according to the process described
below.

25

In an embodiment, the urea derivative (4) is mixed with 4-aminophenol and the reaction
mass is heated to a temperature ranging from 70 to 100°C, preferably from 80 to 90°C.

WO 2009/034308

PCT/GB2008/003048

13

The solvent may be an organic solvent such as water, methylene dichloride (MDC),
ethylene dichloride, tetrahydrofuran (THF), 1,4-dioxane, methyl isobutyl ketone, ethyl
methyl ketone, toluene, N,N-dimethyl formamide (DMF), dimethylsulfoxide (DMSO), ethyl
5 acetate, acetone, acetonitrile or mixtures thereof.

According to another aspect of the present invention, there is provided a process for
preparing urea derivative (4) comprising reacting 3-trifluoromethyl-4-chloroaniline with an
alkali cyanate in the presence of an acid to obtain urea derivative (4)

10

3-trifluoromethyJ-4-chloro
aniline L>ea derivative (4)

wherein M is an alkali metal. In an embodiment, the urea derivative (4) may be used in the
process described above for preparing the compound of formula (1 ).

15

M in the alkali cyanate is an alkali metal such as sodium, potassium, calcium or lithium,
preferably sodium. The alkali cyanate is typically added slowly to 3-trifluoromethyl-4-
chloroaniline suitably at a temperature ranging from 40 to 50°C.

20 The acid may be an organic or inorganic acid. The organic acid may be selected from
acids such as but not limited to acetic acid, oxalic acid, benzoic acid, citric acid, succinic
acid, benzene sulphonic acid, tartaric acid or methane sulphonic acid. The inorganic acid
may be selected from acids such as but not limited to hydrochloric acid, hydrobromic acid,
sulphuric acid, nitric acid or phosphoric acid.

25

WO 2009/034308

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14

According to another aspect of the present invention, there is provided a process for
preparing a compound of formula (1) comprising reacting phenoxy urea (5) with 3-
trifluoromethyl-4-chloroaniline in a solvent in the presence of a base to obtain compound

(1).

5

In an embodiment, the phenoxy urea (5) is prepared according to the process described
below.

10

In an embodiment, the reaction of the phenoxy urea (5) and 3-trifluoromethyl-4-
chloroaniline is carried out at a temperature ranging from 100 to 150°C.

The base used may be an organic or inorganic base. The inorganic base may be selected
15 from potassium tertbutoxide, potassium hydroxide, sodium hydroxide, ammonium
hydroxide, sodium methoxide, potassium methoxide, potassium carbonate, sodium
carbonate and the like. The organic base may be selected from pyridine, dimethyl amine,
triethyl amine, N,N-diisopropylethyl amine and 1,8-diazabicyclo[5.4.0]undec-7-ene.

20 The solvent may be an organic solvent such as water, methylene dichloride (MDC),
ethylene dichloride, tetrahydrofuran (THF), 1,4-dioxane, methyl isobutyl ketone, ethyl
methyl ketone, toluene, N,N-dimethyl formamide (DMF), dimethylsulfoxide (DMSO), ethyl
acetate, acetone, acetonitrile or mixtures thereof.

25 According to another aspect of the present invention, there is provided a process for
preparing phenoxy urea (5) comprising reacting 4-aminophenol

WO 2009/034308

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15

HO

HO

NH,

MOCN

4-aminophenol

Phenoxy urea (5)

wherein M is an alkali metal, with an alkali cyanate in the presence of an acid to obtain
5 phenoxy urea (5). In an embodiment, the phenoxy urea (5) is used in a process described
above for preparing the compound of formula (1).

M in the alkali cyanate is an alkali metal such as sodium, potassium, calcium or lithium,
preferably sodium.

10

The acid may be an organic or inorganic acid. The organic acid may be selected from
acids such as but not limited to acetic acid, oxalic acid, benzoic acid, citric acid, succinic
acid, benzene sulphonic acid, tartaric acid or methane sulphonic acid. The inorganic acid
may be selected from acids such as but not limited to hydrochloric acid, hydrobromic acid,
15 sulphuric acid, nitric acid or phosphoric acid.

The alkali cyanate is typically added slowly to the 4-aminophenol. The reaction may be
carried out at a temperature ranging from 20 to 25°C.

20 According to another aspect of the present invention, there is provided a process for
preparing sorafenib or a salt thereof comprising reacting a compound of formula (1) with 4-
chloro-N-methyl-2-pyridine carboxamide in the presence of a base to obtain sorafenib and
optionally converting sorafenib to a salt thereof.

WO 2009/034308

PCT/GB2008/003048

The base used may be an organic or inorganic base. The inorganic base may be selected
from potassium tertbutoxide, potassium hydroxide, sodium hydroxide, ammonium
5 hydroxide, sodium methoxide, potassium methoxide, potassium carbonate, sodium
carbonate and the like. The organic base may be selected from pyridine, dimethyl amine,
triethyl amine, N,N-diisopropylethyl amine and 1,8-diazabicyclo[5.4.0]undec-7-ene.

The reaction may be carried out at temperature a ranging from 20 to 80°C.

10

In an embodiment, sorafenib is converted to sorafenib tosylate.

In an embodiment, the compound of formula (1) has been prepared according to any one
of the processes described above.

15

According to another aspect of the present invention, there is provided a compound of
formula (6).

20

According to another aspect of the present invention, there is provided a process for
preparing a compound of formula (6) comprising reacting 4-(4-aminophenoxy)-N-
methylpicolinamide or a salt thereof

WO 2009/034308

PCT/GB2008/003048

17

MOCN

H,N

NH

D

NH

4^4^aminophenoxy}- N-

m ethyl pi coli rami de ( V J ^

wherein M is an alkali metal, with an alkali cyanate in the presence of a protic solvent to
obtain compound (6). In an embodiment, the compound of formula (6) is used in the
5 process described above for preparing sorafenib or a salt thereof.

M in the alkali cyanate is an alkali metal such as sodium, potassium, calcium or lithium,
preferably sodium.

10 The protic solvent may be selected from acids such as but not limited to acetic acid, oxalic
acid, benzoic acid, citric acid, succinic acid, benzene sulphonic acid, tartaric acid, methane
sulphonic acid or an inorganic acid. The inorganic acid may be selected from acids such
as but not limited to hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid or
phosphoric acid.

The alkali cyanate may be added to 4-(4-aminophenoxy)-N-methylpicolinamide or its salt
at 20-25°C. The addition of alkali cyanate to 4-(4-aminophenoxy)-N-methylpicolinamide is
typically carried out slowly so as to maintain the desired temperature of the reaction mass
during the addition of the alkali metal cyanate. After addition, the reaction mass may be
20 stirred to obtain intermediate (6).

According to another aspect of the present invention, there is provided a process for
preparing sorafenib or a salt thereof comprising reacting compound (6) with 4-chloro-3-
trifluoromethylaniline in the presence of a base and a solvent to obtain sorafenib and
25 optionally converting sorafenib to a salt thereof.

15

WO 2009/034308 PCT/GB2008/003048

In an embodiment, the base is potassium tert.butoxide, potassium hydroxide, sodium
5 hydroxide, ammonium hydroxide, sodium methoxide, potassium methoxide, potassium
carbonate, sodium carbonate, pyridine, dimethyl amine, triethylamine, N,N-diisopropylethyl
amine or 1 ,8-diazabicyclo[5.4.0]undec-7-ene.

The solvent may include organic solvent such as water, methylene dichloride (MDC),
10 ethylene dichloride, tetrahydrofuan (THF), 1,4-dioxane, methylisobutyl ketone, ethylmethyl
ketone, toluene, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), ethyl acetate,
acetone, acetonitrile or mixtures thereof.

In an embodiment, sorafenib is converted to sorafenib tosylate.

15

In an embodiment, the compound of formula (6) has been prepared according to a
process described above.

According to another aspect of the present invention, there is provided a compound of
20 formula (7).

WO 2009/034308

PCT/GB2008/003048

19

wherein A is alkyl or aryl. In an embodiment, alkyl is C1.3 alkyl, suitably methyl, ethyl, iso-
propyl or n-propyl. In another embodiment aryl is phenyl.

According to another aspect of the present invention, there is provided a process for
5 preparing the compound of formula (7) comprising reacting 4-(4-aminophenoxy)-N-
methylpicolinamide or a salt thereof with a haloformate (2a) or a carbonate derivative (2b)

10

2a

4-(4~aminophenoxy)-N- I
methyl pi cdi rami de (V) ft

2b

A \ JL / A

OR

I

wherein in haloformate (2a), A is alkyl or aryl, and in carbonate (2b), A is alkyl, aryl or the
two A groups taken together form a 5 to 7 membered ring, in the presence of a base to
obtain the compound of formula (7).

15 In an embodiment, the 4-(4-aminophenoxy)-N-methylpicolinamide or a salt thereof is
reacted with the haloformate or a carbonate derivative at a temperature ranging from -5 to
25°C preferably from 0 to 5°C.

In an embodiment, alkyl is C1.3 alkyl, suitably methyl, ethyl, iso-propyl or n-propyl. In
20 another embodiment aryl is phenyl. The carbonate derivative may be an aliphatic
compound. Alternatively, the carbonate derivative may be a cyclic compound, i.e. the two
A groups may be joined to form a ring. In an embodiment, the moiety of the carbonate
joining the two oxygen ring members is -CH2CH2-. In an embodiment, the haloformate or

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20

carbonate derivatives are selected from but not limited to phenyl chloroformate, methyl
chloroformate, ethyl chloroformate, diethyl carbonate and [1 ,3]dioxolan-2-one.

The base used may be an organic or inorganic base. The inorganic base may be selected
5 from potassium tertbutoxide, potassium hydroxide, sodium hydroxide, ammonium
hydroxide, sodium methoxide, potassium methoxide, potassium carbonate, sodium
carbonate and the like. The organic base may be selected from pyridine, dimethyl amine,
triethyl amine, N,N-diisopropylethyl amine and 1,8-diazabicyclo[5.4.0]undec-7-ene.

10 According to another aspect of the present invention, there is provided a process for
preparing sorafenib or a salt thereof comprising reacting compound (7) with 4-chloro-3-
trifluoromethylaniline

wherein A is alkyl or aryl, to obtain sorafenib and optionally converting the sorafenib to a
salt thereof. In an embodiment, alkyl is C1-3 alkyl, suitably methyl, ethyl, iso-propyl or n-
propyl. In another embodiment aryl is phenyl.

20 The reaction may be carried out in a solvent which may include water or an organic
solvent such as methylene dichloride (MDC), ethylene dichloride, tetrahydrofuran (THF),
1,4-dioxane, methyl isobutyl ketone, ethyl methyl ketone, toluene, N,N-dimethyl formamide
(DMF), dimethylsulfoxide (DMSO), ethyl acetate, acetone, acetonitrile or mixtures thereof.

o

+

NH

15

25 The reaction mass may be heated to the reflux temperature of the solvent.

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21

According to another aspect of the present invention, there is provided a compound of
formula (8)

G

5

wherein X is halogen. Halogen may be selected from chlorine, bromine or iodine,
preferably chlorine.

According to another aspect of the present invention, there is provided a process for
10 preparing a compound of formula (8) comprising reacting 4-(4-aminophenoxy)-N-
methylpicolinamide or a salt thereof with a trihaloalkyl halide, a trihaloanhydride or a trihalo
ester

O

4.(*aminophenoxy}-N- CXSCO^O OR

methyl pi cdinamids (V) CXjCOOR ^

15

wherein X is halogen, to obtain the compound of formula (8). In an embodiment, the
compound (8) is used in the process described above for preparing sorafenib or a salt
thereof.

20 X in trihaloalkyl halide or anhydride or ester is halogen such as chlorine, bromine, iodine,
preferably chlorine. The trihaloalkyl halide or anhydride or ester may be selected from the
group consisting of trichloroacetyl chloride, tribromoacetyl chloride, trichloroacid anhydride,

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22

ethyl trichloroacetate, methyl trichloroacetate, phenyl trichloroacetate, ethyl
tribromoacetate.

The trihaloalkyl halide or anhydride or ester is typically added slowly to 4-(4-
5 aminophenoxy)-N-methyl picolinamide so as to maintain the desired temperature of the
reaction mass during addition of the trihaloalkyl halide or anhydride or ester. The
temperature at which reaction is carried out may range from 0 to 150°C. The reaction is
optionally carried out in the presence of a base.

10 According to another aspect of the present invention, there is provided a process for
preparing sorafenib or a salt thereof comprising reacting compound (8) with 4-chloro-3-
trifluoromethylaniline

+-cMcfo->lrMiJorome Ixrlarltne
LSD + SORAFENIB (|)

15

wherein X is halogen, in the presence of a base to obtain sorafenib and optionally
converting the sorafenib to a salt thereof. In an embodiment, the compound (8) is prepared
according to the process described above. X is halogen such as chlorine, bromine or
iodine, preferably chlorine.

20

The reaction may be carried out in the presence of a solvent which may include organic
solvent such as water, methylene dichloride (MDC), ethylene dichloride, tetrahydrofuran
(THF), 1,4-dioxane, methyl isobutyl ketone, ethyl methyl ketone, toluene, N,N-dimethyl
formamide (DMF), dimethylsulfoxide (DMSO), ethyl acetate, acetone, acetonitrile or
25 mixtures thereof.

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The base used may be an organic or inorganic base. The inorganic base may be selected
from potassium tertbutoxide, potassium hydroxide, sodium hydroxide, ammonium
hydroxide, sodium methoxide, potassium methoxide, potassium carbonate, sodium
carbonate and the like. The organic base may be selected from pyridine, dimethyl amine,
5 triethyl amine, N,N-diisopropylethyl amine and 1,8-diazabicyclo[5.4.0]undec-7-ene.

In an embodiment, the reaction is carried out at a temperature ranging from 100 to 150°C.

According to another aspect of the present invention, there is provided a process for
10 preparing sorafenib or a salt thereof comprising condensing 4-(4-aminophenoxy)-N-
methylpicolinamide or a salt thereof with carbamate derivative (2) (which is the same as
carbamate derivative (2) described above)

15

wherein A is alkyl or aryl, to obtain sorafenib and optionally converting the sorafenib to a
salt thereof. In an embodiment, alkyl is C1-3 alkyl, suitably methyl, ethyl, iso-propyl or n-
propyl. In another embodiment, aryl is phenyl.

20 The reaction mass may be stirred at a temperature ranging from 30 to 50°C to obtain the
final product.

The reaction may be carried out in the presence of a solvent which may include organic
solvent such as water, methylene dichloride (MDC), ethylene dichloride, tetrahydrofuran
25 (THF), 1,4-dioxane, methyl isobutyl ketone, ethyl methyl ketone, toluene, N,N-dimethyl

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formamide (DMF), dimethylsulfoxide (DMSO), ethyl acetate, acetone, acetonitrile or
mixtures thereof.

In an embodiment, the carbamate derivative (2) is prepared according to the process
5 described above.

According to another aspect of the present invention, there is provided a process for
preparing sorafenib or a salt thereof comprising condensing 4-(4-aminophenoxy)-N-
methylpicolinamide or a salt thereof with an anilide derivative of formula (3) (which is the
10 same as anilide derivative (3) described above)

A rilide derivative (3) 4-(4.aminophenoxy>N-

. methyipicolinamide

H H

SORAFENIB (I)

15 wherein X is halogen, in the presence of a base to obtain sorafenib and optionally
converting the sorafenib to a salt thereof. X is halogen such as chlorine, bromine or
iodine, preferably chlorine.

The base used may be an organic or inorganic base. The inorganic base may be selected
20 from potassium tertbutoxide, potassium hydroxide, sodium hydroxide, ammonium
hydroxide, sodium methoxide, potassium methoxide, potassium carbonate, sodium
carbonate and the like. The organic base may be selected from pyridine, dimethyl amine,
triethyl amine, N,N-diisopropylethyl amine and 1,8-diazabicyclo[5.4.0]undec-7-ene.

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The reaction may be carried out in the presence of a solvent, which may include organic
solvent such as water, as methylene dichloride (MDC), ethylene dichloride, tetrahydrofuran
(THF), 1,4-dioxane, methyl isobutyl ketone, ethyl methyl ketone, toluene, N,N-dimethyl
5 formamide (DMF), dimethylsulfoxide (DMSO), ethyl acetate, acetone, acetonitrile or
mixtures thereof.

The reaction may be carried out at a temperature ranging from 100 to 150°C.

10 In an embodiment, the anilide derivative (3) is prepared according to the process
described above.

According to another aspect of the present invention, there is provided a process for
preparing sorafenib or a salt thereof comprising condensing 4-(4-aminophenoxy)-N-
15 methylpicolinamide or a alt thereof with urea derivative (4) (which is the same as the urea
derivative (4) described above)

H H

SORAFENIB (I)

20

in the presence of a base to obtain sorafenib, and optionally converting the sorafenib to a
salt thereof.

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The base used may be an organic or inorganic base. The inorganic base may be selected
from potassium tertbutoxide, potassium hydroxide, sodium hydroxide, ammonium
hydroxide, sodium methoxide, potassium methoxide, potassium carbonate, sodium
5 carbonate and the like. The organic base may be selected from pyridine, dimethyl amine,
triethyl amine, N,N-diisopropylethyl amine and 1,8-diazabicyclo[5.4.0]undec-7-ene.

The reaction may be carried out in the presence of a solvent, which may include an
organic solvent such as water, methylene dichloride (MDC), ethylene dichloride,
10 tetrahydrofuran (THF), 1,4-dioxane, methyl isobutyl ketone, ethyl methyl ketone, toluene,
N,N-dimethyl formamide (DMF), dimethylsulfoxide (DMSO), ethyl acetate, acetone,
acetonitrile or mixtures thereof

The reaction may be carried out at a temperature ranging from 100 to 150°C.

15

In an embodiment, the urea derivative (4) is prepared according to the process described
above.

According to another aspect of the present invention, there is provided a compound of
20 formula (9)

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According to another aspect of the present invention, there is provided a process for
preparing hydroxy urea derivative (9) (i.e. the compound (A) in which R' is -C(O)-NHOH)
comprising reacting carbamate derivative (2) with a hydroxyl amine in a protic solvent.

5

The hydroxyl amine is suitably used as its salt, for example its hydrochloride salt.
10 Carbamate derivative (2) and the hydroxyl amine salt may be mixed and then heated to
the reflux temperature of the solvent.

The protic solvent may be selected from acids such as but not limited to acetic acid, oxalic
acid, benzoic acid, citric acid, succinic acid, benzene sulphonic acid, tartaric acid, methane
15 sulphonic acid or an inorganic acid. The inorganic acid may be selected from acids such
as but not limited to hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid or
phosphoric acid.

According to another aspect of the present invention, there is provided a process for
20 preparing sorafenib or a salt thereof comprising condensing 4-(4-aminophenoxy)-N-
methylpicolinamide or a salt thereof with hydroxyl urea derivative (9) (i.e. the compound
(A) in which R' is -C(O)-NHOH)

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5 to obtain sorafenib, and optionally converting the sorafenib to a salt thereof.

The reaction is typically carried out in the presence of a base. The base used may be an
organic or inorganic base. The inorganic base may be selected from potassium
tertbutoxide, potassium hydroxide, sodium hydroxide, ammonium hydroxide, sodium
10 methoxide, potassium methoxide, potassium carbonate, sodium carbonate and the like.
The organic base may be selected from pyridine, dimethyl amine, triethyl amine, N,N-
diisopropylethyl amine and 1,8-diazabicyclo[5.4.0]undec-7-ene.

The reaction may be carried out at a temperature ranging from 100 to 150°C.

15

Sorafenib prepared according to any one of the processes described above forms another
aspect of the present invention.

The salt of sorafenib prepared according to any one of the processes described above
20 forms another aspect of the present invention.

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According to another aspect of the present invention, there is provided a pharmaceutical
composition comprising sorafenib or a salt thereof as prepared according to any one of the
processes described above, together with at least one pharmaceutical^ acceptable
excipient. Such pharmaceutical compositions and excipient(s) are well known to those
5 skilled in the art.

According to another aspect of the present invention, there is provided the use of
sorafenib or a salt thereof as prepared according to any one of the processes described
above in medicine.

10

According to another aspect of the present invention, there is provided the use of
sorafenib or a salt thereof as prepared according to any one of the processes described
above in treating renal cell carcinoma or advanced hepatocellular carcinoma.

15 According to another aspect of the present invention, there is provided the use of
sorafenib or a salt thereof as prepared according to any one of the processes described
above in the manufacture of a medicament for treating renal cell carcinoma or advanced
hepatocellular carcinoma.

20 According to another aspect of the present invention, there is provided a method for the
treatment of renal cell carcinoma or advanced hepatocellular carcinoma comprising
administering to a patient in need thereof a therapeutically effective amount of sorafenib or
a salt thereof as prepared according to any one of the processes described above.

25 Detailed Description of the Invention

The present invention relates to novel key intermediates useful in the synthesis of
sorafenib or its pharmaceutically acceptable salts.

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30

In an embodiment, intermediate (1) of the present invention is obtained by a process
comprising the steps of:

a) reacting 3-trifluoromethyl-4-chloroaniline with a haloformate, such as chloroformate, or
a carbonate derivative in the presence of a base and a suitable solvent and at a suitable

5 temperature to obtain carbamate derivative (2).

b) reacting carbamate derivative (2) with 4-aminophenol in the presence of a suitable
organic solvent to obtain intermediate (1). The reaction is represented by Scheme III.

Scheme III

o

A

O
I

A

NH 2

3- trifluoromethyl-

4- chloroaniline

OR o

A = R or Ar
X = Halogen

HO

p-aminophenol

Carbamate derivative
(2)

CF 3

as

iXix

N N
H H

^ in

10

A in the haloformate or carbonate derivative may be alkyl (R) or aryl (Ar) wherein alkyl is
C1-3 alkyl, suitably methyl, ethyl, iso-propyl or n-propyl, and aryl is preferably phenyl. The
carbonate derivative may be an aliphatic or cyclic compound (i.e. the two A groups taken
together form a ring). Examples of haloformate or carbonate derivatives which can be
15 used are selected from but not limited to phenyl chloroformate, methyl chloroformate, ethyl
chloroformate, diethyl carbonate, [1 ,3]dioxolan-2-one and the like.

The base used may be an organic or inorganic base. The inorganic base may be selected
from potassium tertbutoxide, potassium hydroxide, sodium hydroxide, ammonium
20 hydroxide, sodium methoxide, potassium methoxide, potassium carbonate, sodium
carbonate and the like. The organic base may be selected from pyridine, dimethyl amine,
triethyl amine, N,N-diisopropylethyl amine and 1,8-diazabicyclo[5.4.0]undec-7-ene.

The reaction of 3-trifluoromethyl-4-chloroaniline with the haloformate or carbonate
25 derivative may be carried out at a temperature ranging from -10 to 25°C, preferably from -

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31

5 to 5°C. Typically, the haloformate or carbonate derivative is added slowly so as to
maintain the temperature of the reaction mass.

The reaction of carbamate derivative (2) with 4-aminophenol is carried out at a higher
5 temperature ranging from 0 to 60°C, preferably from 40 to 60°C wherein the mixture of
carbamate derivative and 4-aminophenol is heated to the temperature ranging from 40 to

Suitable solvent may include organic solvents such as water, methylene dichloride (MDC),
10 ethylene dichloride, tetrahydrofuran (THF), 1,4-dioxane, methyl isobutyl ketone, ethyl
methyl ketone, toluene, N,N-dimethyl formamide (DMF), dimethylsulfoxide (DMSO), ethyl
acetate, acetone, acetonitrile or mixtures thereof.

In another embodiment of the present invention, intermediate (1) may be obtained by the
15 process comprising steps of:

a) reacting 3-trifluoromethyl-4-chloroaniline with a trihaloalkyl halide such as a trihaloalkyl
chloride, or a trihaloalkyl anhydride or a trihaloalkyl ester to obtain anilide derivative (3).

b) reacting anilide derivative (3) with 4-aminophenol in a suitable organic solvent at a
suitable temperature to obtain intermediate (1). The reaction is represented by Scheme IV.

60°C.

20

Scheme IV

o

OR *
(CX3CO) 2 0 OR
CX3COOR

CI

CI

X

o

HO

OH

CI

Trihaloalkyl halide
or anhydride or ester

v N CX^
H 3

Anilide derivative (3)

p-aminophenol

3-trifluoromethyl-4-
chloroaniline

N
H

N
H

d)

X in trihaloalkyl halide or anhydride or ester is halogen such as chlorine, bromine or iodine,
preferably chlorine. R has the same meaning as defined for Scheme III above. The
25 trihaloalkyl halide or anhydride or ester used is selected from but not limited to

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32

trichloroacetyl chloride, tribromoacetyl chloride, trichloro acid anhydride, ethyl
trichloroacetate, methyl trichloroacetate, phenyl trichloroacetate, ethyl tribromoacetate,
and the like. The reaction of the trihaloalkyl haiide or anhydride or ester is carried out at a
temperature ranging from -5 to 25°C. Typically, the trihaloalkyl haiide or anhydride or ester
5 is added slowly so as to maintain the desired temperature of the reaction mass during
addition of the trihalo compound.

The reaction of anilide derivative (3) with 4-aminophenol is carried out at a higher
temperature ranging from 100 to 140°C, preferably from 110 to 120°C wherein the mixture
10 of anilide derivative and 4-aminophenol is heated to the temperature ranging from 110 to
120°C.

Optionally, the reaction steps are carried out in the presence of a base. The base may be
an organic or inorganic base as described for Scheme III above.

15

The suitable solvent may be an organic solvent as described for Scheme III above.

In an alternative embodiment, intermediate (1) may be made via another process which
comprises the steps:

20 a) reacting 3-trifluoromethyl-4-chloroaniline with an alkali cyanate in acidic conditions at a
suitable temperature to obtain urea derivative (4); and

b) reacting urea derivative (4) with 4-aminophenol in a suitable organic solvent at a
suitable temperature to obtain intermediate (1). The reaction is represented by Scheme V.

Scheme V

25 chloroaniline

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M in the alkali cyanate is an alkali metal such as sodium, potassium, calcium or lithium,
preferably sodium. The alkali cyanate is typically added slowly to 3-trifluoromethyl-4-
chloroaniline suitably at a temperature ranging from 40 to 50°C. The acid may be an
5 organic or inorganic acid. The organic acid may be selected from acids such as but not
limited to acetic acid, oxalic acid, benzoic acid, citric acid, succinic acid, benzene
sulphonic acid, tartaric acid or methane sulphonic acid. The inorganic acid may be
selected from acids such as but not limited to hydrochloric acid, hydrobromic acid,
sulphuric acid, nitric acid or phosphoric acid.

10

The urea derivative obtained in step a) is mixed with 4-aminophenol and the reaction mass
is typically heated to a temperature ranging from 70 to 100°C, preferably from 80 to 90°C.

Suitable solvents used for both the steps are organic solvents as described for scheme III
1 5 above.

In an yet another embodiment, intermediate (1) may be made via another process which
comprises the steps:

a) reacting 4-aminophenol with an alkali cyanate in acidic conditions at a suitable
20 temperature to obtain phenoxy urea (5); and

b) reacting phenoxy urea (5) with 3-trifluoromethyl-4-chloroaniline in a suitable organic
solvent at a suitable temperature in the presence of a base to obtain intermediate (1). The
reaction is represented by Scheme VI.

Scheme VI

25

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The alkali cyanate and acid used in step a) are the same as described in step a) of
Scheme V above. The alkali cyanate is typically added slowly to the 4-aminophenol. The
reaction may be carried out at a temperature ranging from 20 to 25°C.

5

The reaction of the phenoxy urea (5) and 3-trifluoromethyl-4-chloroaniline is suitably
carried out at a temperature ranging from 100 to 150°C. The base and the solvents used
are the same as described for Scheme Ml above.

10 In another embodiment, there is provided an intermediate of formula (1).

T 3

fl o

H H

A schematic representation of various processes for the preparation of novel intermediate
15 (1) is as follows :

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Scheme III

35

(3)

Scheme IV

CF 3

H H

^ (D

Scheme VI

HO

H

(5)

Scheme V

In another aspect of the present invention, intermediate (1) is used in the synthesis of
sorafenib. In an embodiment, intermediate (1 ) is reacted with 4-chloro-N-methyl-2-pyridine
carboxamide in the presence of a base at a suitable temperature. The reaction is
represented by Scheme VII.

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O

4-ch I oro-N-m ethyl
-2-pyridine carboxamide

H H

SORAFENIB (|)

The base may be the same as that described for scheme III above. The reaction may be
carried out at a temperature ranging from 20 to 80°C.

5

The advantage of this process is that it gives a good yield and purity of sorafenib.

According to another aspect of the present invention, there is provided novel intermediate
(6).

10

According to another aspect of the present invention, intermediate (6) is used in the
preparation of sorafenib. In an embodiment, the process comprises the steps of:
a) reacting 4-(4-aminophenoxy)-N-methylpicolinamide or a salt thereof with an alkali
cyanate in the presence of a protic solvent at a suitable temperature to obtain intermediate
15 (6); and

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b) reacting intermediate (6) with 3-trifluoromethyl-4-chloroaniline in the presence of a base
and an organic solvent at a suitable temperature to obtain sorafenib. The reaction is
represented by Scheme Ilia below.

5 M in the alkali cyanate in Scheme Ilia is an alkali metal such as sodium, potassium,
calcium or lithium, preferably sodium. The protic solvent may be selected from acids such
as but not limited to acetic acid, oxalic acid, benzoic acid, citric acid, succinic acid,
benzene sulphonic acid, tartaric acid, methane sulphonic acid or an inorganic acid. The
inorganic acid may be selected from acids such as but not limited to hydrochloric acid,
10 hydrobromic acid, sulphuric acid, nitric acid or phosphoric acid.

The alkali cyanate may be added to 4-(4-aminophenoxy)-N-methylpicolinamide or its salt
at 20-25°C. The addition of alkali cyanate to 4-(4-aminophenoxy)-N-methylpicolinamide is
typically carried out slowly so as to maintain the desired temperature of the reaction mass
15 during addition of the alkali cyanate. After addition, the reaction mass may be stirred to
obtain intermediate (6).

Intermediate (6) is then reacted with 3-trifluoromethyl-4-chloroaniline in the presence of a
base such as but not limited to potassium tert.butoxide, potassium hydroxide, sodium

20 hydroxide, ammonium hydroxide, sodium methoxide, potassium methoxide, potassium
carbonate, sodium carbonate, pyridine, dimethyl amine, triethylamine, N,N-diisopropylethyl
amine or 1 ,8-diazabicyclo[5.4.0]undec-7-ene. The suitable solvent may be an organic
solvent such as water, methylene dichloride (MDC), ethylene dichloride, tetrahydrofuan
(THF), 1,4-dioxane, methylisobutyl ketone, ethylmethyl ketone, toluene, N,N-

25 dimethylformamide (DMF), dimethylsulfoxide (DMSO), ethyl acetate, acetone, acetonitrile
or mixtures thereof.

The reaction mass may be heated to the reflux temperature of the solvent.

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In another embodiment of the present invention, sorafenib is prepared by a process
comprising the steps:

a) reacting 4-(4-aminophenoxy)-N-methylpicolinamide or a salt thereof with a haloformate
such as chloroformate or a carbonate derivative in the presence of a base at a suitable

5 temperature to obtain intermediate (7); and

b) reacting intermediate (7) with 3-trifluoromethyl-4-chloroaniline to obtain sorafenib. The
reaction is represented by Scheme IVa below.

4-(4-aminophenoxy)-N-methylpicolinamide is reacted with a haloformate or a carbonate
10 derivative in the presence of the base typically at a temperature ranging from -5 to 25°C
preferably from 0 to 5°C.

A in the haloformate or carbonate derivative may be alkyl (R) or aryl (Ar) wherein alkyl is
C1-3 alkyl, suitably methyl, ethyl, iso-propyl or n-propyl, and aryl is preferably phenyl. The
15 carbonate derivative may be an aliphatic or cyclic compound (i.e. the two A groups taken
together form a ring). Examples of haloformate or carbonate derivatives which can be
used are selected from but not limited to phenyl chloroformate, methyl chloroformate, ethyl
chloroformate, diethyl carbonate, [1 ,3]dioxolan-2-one and the like.

20 The base used is the same as the base described for Scheme Ilia above.

Intermediate (7) is then mixed with 3-trifluoromethyl-4-chloroaniline in an organic solvent in
the same way as described above in relation to Scheme Ilia. The reaction mass may be
heated to the reflux temperature of the solvent.

25

In yet another embodiment of the present invention, sorafenib may also be prepared by a
process comprising the steps:

a) reacting 4-(4-aminophenoxy)-N-methylpicolinamide or a salt thereof with a trihaloalkyl
halide for example a trihaloalkyl chloride, or a trihaloanhydride or a trihalo ester at a
30 suitable temperature to obtain intermediate (8); and

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b) reacting intermediate (8) with 3-trifluoromethyl-4-chloroaniline to obtain sorafenib. The
reaction is represented by Scheme Va.

X in trihaloalkyl halide or anhydride or ester is halogen such as chlorine, bromine, iodine,
5 preferably chlorine. The trihaloalkyl halide or anhydride or ester may be selected from the
group consisting of trichloroacetyl chloride, tribromoacetyl chloride, trichloroacid anhydride,
ethyl trichloroacetate, methyl trichloroacetate, phenyl trichloroacetate, ethyl
tri b ro m oacetate .

10 The trihaloalkyl halide or anhydride or ester is typically added slowly to 4-(4-
aminophenoxy)-N-methyl picolinamide so as to maintain the desired temperature of the
reaction mass during addition of the trihalo compound. The temperature at which reaction
is carried out may range from 0 to 150°C. The reaction is optionally carried out in the
presence of a base.

15

Intermediate (8) is then mixed with 3-trifluoromethyl-4-chloroaniline in an organic solvent in
the same way as described above in relation to Scheme Ilia typically at an elevated
temperature ranging from 100 to 150°C. The reaction is carried out in presence of a base.
The base used is the same as described in relation to Scheme Ilia above.

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40

Scheme Ilia Scheme IVa Scheme Va

o

3-trifluoromethyi-4-chloroaniline

H H

SORAFENIB (i)

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41

In another embodiment of the present invention, sorafenib is alternatively prepared by
condensing 4-(4-aminophenoxy)-N-methylpicolinamide or a salt thereof with a carbamate
derivative (2). The solvent used in the reaction is the same as described above in relation
to Scheme Ilia above. The reaction mass may be stirred at a temperature ranging from 30
5 to 50°C to obtain the final product. The reaction is represented by Scheme Via. The
carbamate derivative (2) is the same as the carbamate derivative used in Scheme III
above.

The carbamate derivative (2) may be prepared by reacting 3-trifluoromethyl-4-chloroaniline
10 with a haloformate such as a chloroformate or carbonate derivative in the presence of a
base as described in relation to scheme Ilia above. Addition of the haloformate or
carbonate derivative to 3-trifIuoromethyl-4-chloroaniline is typically carried out slowly so as
to maintain the desired temperature of the reaction mass during addition of the alkali
cyanate. The temperature at which reaction is carried out may be in the range from -10 to
15 25°C.

■>

In yet another embodiment of the present invention sorafenib is alternatively prepared by
condensing 4-(4-aminophenoxy)-N-methylpicolinamide with a urea derivative (4) in the
presence of a base. The reaction may involve mixing 4-(4-aminophenoxy)-N-
20 methylpicolinamide or a salt thereof with urea derivative (4) in a suitable solvent at a
temperature ranging from 100 to 150°C. Further, the reaction is carried out in presence of
a base. The base and the solvent used are the same as described in relation to Scheme
Ilia above. The reaction is represented by Scheme Vila. The urea derivative (4) is the
same as the urea derivative used in Scheme V above.

25

Urea derivative (4) may be prepared by reacting 3-trifluoromethyl-4-chloroaniline or an
acid addition salt thereof with an alkali cyanate in the presence of a protic solvent. The
alkali cyanate and protic solvent are the same as described above in relation to Scheme
Ilia. The alkali cyanate is typically added slowly to 3-trifluoromethyl-4-chloroaniline at a
30 temperature ranging from 40 to 50°C.

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In yet another alternative embodiment of the present invention sorafenib is alternatively
prepared by condensing 4-(4-aminophenoxy)-N-methylpicolinamide or a salt thereof with
anilide derivative (3). Typically, the reaction is carried out in a suitable solvent and in the
5 presence of a base optionally at a temperature ranging from 100 to 150°C. The solvent
and the base used is the same as described above in relation to Scheme Ilia. The reaction
is represented by Scheme Villa. The anilide derivative (3) is the same as the anilide
derivative used in Scheme IV above.

10 Anilide derivative (3) may be obtained by reacting 3-trifluoromethyl-4-chloroaniline with a
trihaloalkyl halide such as a trihaloalkyl chloride or a trihaloanhydride or a trihalo ester.
The reaction of the trihaloalkyl halide or anhydride or ester is typically carried out at a
temperature ranging from -5 to 25°C. Suitably, the trihaloalkyl halide or anhydride or ester
is added slowly so as to maintain a constant temperature of the reaction mass during

15 addition of the trihaloalkyl halide or anhydride or ester. Optionally the reaction is carried
out in presence of a base. The base and the solvent used are the same as described
above in relation to Scheme Ilia.

In yet another embodiment of the present invention, sorafenib is prepared by condensing
20 4-(4-aminophenoxy)-N-methylpicolinamide or a salt thereof with hydroxy urea derivative
(9). The reaction is typically carried out in the presence of a base as described above in
relation to Scheme Ilia and optionally at a temperature ranging from 100 to 150°C. The
reaction is represented by Scheme IX.

25 Hydroxy urea derivative (9) may be obtained by reacting carbamate derivative (2) with a
hydroxyl amine in a protic solvent. The hydroxyl amine is suitably used as its salt, for
example its hydrochloride salt. Carbamate derivative (2) and the hydroxyl amine salt may
be mixed and then heated to the reflux temperature of the solvent. The protic solvent is the
same as described above in relation to Scheme Ilia.

30

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o

Scheme Via Scheme Vila Scheme Villa Scheme IX

H ' H

SORAFENIB (I)

5

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The synthesis of intermediates (2), (3) & (4) is shown below in Scheme X.

Scheme X

4-chloro-3-trifluoro
methyaniline

O

A = R or Ar
X = Halogen

MOCN / H+

O

A

O— A

cx.

fc 3 OR
Trihaloalkyl halide

or anhydride or ester (CX3CO) 2 0 OR

Carbamate derivative
(2)

o

x

H

Urea derivative
(4)

Anilide derivative
(3)

CX 3 COOR

The synthesis of intermediate (9) is shown below in Scheme XL

Scheme XI

Carbamate derivative (4)

Hydroxy urea derivative (9)

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Optionally, the sorafenib may be converted into a pharmaceutical^ acceptable salt
thereof, more specifically into its tosylate salt. The tosylate salt of sorafenib may be
prepared by reaction with p-toluene sulfonic acid.

5

The present invention is now further illustrated by the following examples, which do not, in
any way, limit the scope of the invention.

Examples

10

Example 1: Synthesis of phenyl 4-chloro-3-(trifiuoromethyl)phenylcarbamate
(Compound 2)

3-trifluoromethyl-4-chloroaniline (25 g, 0.1278 mol) and pyridine (26 ml, 0.3195 mol) were
1 5 dissolved in dichloromethane (250 ml). The reaction mass was cooled to 0°C to -5°C and
a solution of phenyl chloroformate (22 ml, 0.1661 mol) in dichloromethane (100 ml) was
added drop wise maintaining the temperature of the reaction mass below 0°C. The
reaction mass was stirred at 0°C to 5°C for 1-2 hours and quenched with water (200 ml)
below 10°C.The organic phase was separated and washed with water followed by 1N HCI.
20 It was then dried over sodium sulfate and concentrated to obtain solid. This solid was
agitated with hexane (350 ml) at ambient temperature for 2-3 hours and filtered. The
obtained product was vacuum dried at 50°C to give phenyl 4-chloro-3-
(trifluoromethyl)phenylcarbamate (36 g) as white solid.

25 Example 2: Synthesis of 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-
hydroxyphenyl)urea (Compound 1)

To the dry N,N-dimethyl formamide (150 ml) phenyl 4-chloro-3-
(trifluoromethyl)phenylcarbamate (50 g, 0.15873 mol) and p-amino phenol (20.78 g,
30 0.1904 mol) were added at room temperature. The reaction mass was then heated to

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50°C for 4-6 hours and cooled to room temperature. Water (500 ml) was added and the
obtained mass was extracted with ethyl acetate and the combined extracts were washed
with water. It was dried over sodium sulfate and concentrated to obtain semi solid. The
residue was then charged with acetonitrile (700 ml) and the obtained precipitate was
5 stirred at ambient temperature for 2-3 hours. The solid was filtered and washed thoroughly
with acetonitrile till clear filtrate was obtained. The solid thus obtained was dried in vacuum
oven at 50°C to afford the desired 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-
hydroxyphenyl)urea (40 g).

10 Example 3: Synthesis of 2,2,2-trichloro-N-(4-chloro-3-(trifluoromethyl)phenyl)
acetamide (Compound 3)

The clear solution of 3-trifluoromethyl-4-chloroaniline (35 g, 0.1789 mol) and pyridine (36
ml, 0.447 mol) in dichloromethane (350 ml) was cooled at 0°C to -5°C and a solution of

15 trichloro acetyl chloride (26ml, 0.2326 mol) in dichloromethane (75 ml) was added drop
wise maintaining temperature of the reaction mass below 0°C. The reaction mass was
stirred for 1 hour below 0°C and quenched with water (150 ml) below 5°C. The organic
phase was separated and aqueous layer was reextracted with dichloromethane. The
combined dichloromethane layer was then washed with water, dried over sodium sulfate

20 and evaporated under vacuum to obtain (55 g) the desired product i.e. 2,2,2-trichloro-N-(4-
chloro-3-(trifluoromethyl) phenyl) acetamide.

Example 4: Synthesis of 2,2,2-trichloro-N-(4-chloro-3-(trifluoromethyl)phenyl)
acetamide (Compound 3)

25

The clear solution of 3-trifluoromethyl-4-chloroaniline (35 g, 0.1789 mol) and pyridine (36
ml, 0.447 mol) in dichloromethane (350 ml) was cooled at 0°C to -5°C and a solution of
trichloro acid anhydride (42.8 ml, 0.2345 mol) in dichloromethane (75 ml) was added drop
wise maintaining temperature of the reaction mass below 0°C. The reaction mass was
30 stirred for 1 hour below 0°C and quenched with water (150 ml) below 5°C. The organic

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phase was separated and aqueous layer was reextracted with dichloromethane. The
combined dichloromethane layer was then washed with water, dried over sodium sulfate
and evaporated under vacuum to obtain (52 g) the desired product i.e. 2,2,2-trichloro-N-(4-
chloro-3-(trifluoromethyl)phenyl) acetamide.

5

Example 5: Synthesis of 2,2,2-trichloro-N-(4-chloro-3-(trifluoromethyl) phenyl)
acetamide (Compound 3)

3-trifluoromethyl-4-chloroaniline (50 g, 0.255 mol) was mixed with ethyi-2,2,2-trichloro
10 acetate (150 ml) in toluene (500 ml) at room temperature. The mixture was refluxed for 2-3
hours. The organic solvent was degassed under reduced pressure to obtain oil. This oil
was stirred with hexane to obtain the desired product (79 g) i.e. 2,2,2-trichloro-N-(4-chloro-
3-(trifluoromethyl)phenyl) acetamide.

15 Example 6: Synthesis of 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-
hydroxyphenyl)urea (Compound 1)

2,2,2-trichloro-N-(4-chloro-3-(trifluoromethyl) phenyl) acetamide (25 g, 0.07338 mol) was
dissolved in dimethyl formamide (75 ml). 1,8-diazabicyclo[5.4.0]undec-7-ene (17.5 ml,

20 0.1 1731 mol) and 4-amino phenol (9.6 g, 0.0879 mol) were added in one lot. The reaction
mass was heated to 110-120°C for 18-20 hours, cooled to room temperature and
quenched in water (750 ml). The quenched mass was extracted repeatedly with ethyl
acetate and the combined ethyl acetate layer was then back washed with water. It was
then dried over sodium sulfate and evaporated under vacuum to obtain solid. The obtained

25 solid was slurried in acetonitrile (300 ml) at ambient temperature and filtered to give 1-(4-
chloro-3-(trifluoromethyl)phenyl)-3-(4-hydroxyphenyl)urea (18 g).

Example 7: Synthesis of 1-(4-chloro-3-(trifluoromethyl)phenyl)urea (Compound 4)

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Sodium cyanate (1.7 g, 0.02 mol) was dissolved in water (17 ml) at room temperature to
obtain a clear solution. This solution was then charged drop wise to the clear solution of 3-
trifluoromethyl-4-chloro aniline (5 g, 0.025 mol) in acetic acid (25 ml) at 40°C-45°C within
1-2 hours. The reaction mass was then agitated for whole day cooling gradually to room
5 temperature. The obtained solid was then filtered, washed with water and vacuum dried at
50°C to afford (4.5 g) the desired product i.e. 1-(4-chloro-3-(trifluoromethyl)phenyl)urea.

Example 8: Synthesis of 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-
hydroxyphenyl)urea (Compound 1)

10

1-(4-chloro-3-(trifluoromethyl)phenyl)urea (100 g, 0.04191 mol), 1 ,8-
diazabicyclo[5.4.0]undec-7-ene (9.4 ml, 0.0628 mol) and 4-amino phenol (5.48 g, 0.050
mol) were mixed with dimethyl sulfoxide (25 ml) and the reaction mass was heated to 80°-
90°C for 8-9 hours. It was then cooled to room temperature and quenched in water (150

15 ml). The quenched mass was extracted repeatedly with ethyl acetate and the combined
ethyl acetate layer was then back washed with water. The residue was then dried over
sodium sulfate and evaporated under vacuum to obtain solid. The solid thus obtained was
then slurried in acetonitrile (100 ml) at ambient temperature and filtered. It was washed
repeatedly with acetonitrile till clear filtrate was obtained. The obtained cake was suck

20 dried for 10 minutes and vacuum dried at 50°C to give 1-(4-chloro-3-
(trifluoromethyl)phenyl)-3-(4-hydroxyphenyl)urea (9.8 g).

Example 9: Synthesis of 1-(4-hydroxyphenyl)urea (Compound 5)

25 4-aminophenol (45 g, 0.4123 mol) was charged in water and acetic acid mixture (9:1) (450
vol) to obtain a clear solution. To this clear solution was added drop wise previously
prepared solution of sodium cyanate (29.48 g, 0.45358 mol) in water over a period of 1
hour. The reaction mass obtained was stirred for 6 hours at ambient temperature and
filtered to obtain solid. The solid was washed with water and vacuum dried to obtain the

30 desired product i.e. 1-(4-hydroxyphenyl)urea. (48 g)

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Example 1 0 : Synthesis of 1 -(4-chloro-3-(trif luoromethyl)phenyl)-3-(4-
hydroxyphenyl)urea (Compound 1)

To the dry N,N-dimethylformamide (45 ml) and 1-(4-hydroxyphenyl)urea (15 g, 0.0985
5 mol) solution were added triethylamine (34 ml, 0.24646 mol) and 3-trifluoromethyl-4-
chloroaniline (19.28 g, 0.0985 mol) in one lot. This reaction mass was then agitated at
100°C for 10-12 hours, quenched in water and the aqueous layer was extracted with ethyl
acetate. The ethyl acetate layer was back washed with water and dried over sodium
sulfate. It was evaporated under vacuum to obtain solid. The obtained solid was slurried in
10 acetonitrile (100 ml) at ambient temperature, filtered and washed repeatedly with
acetonitrile till the clear filtrate was obtained. The obtained cake was then suck dried for 10
minutes and vacuum dried at 50°C to give 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-
hydroxyphenyl)urea (25 g).

15 Example 11: Synthesis of 4-(4-{3-[4-Chloro-3-

(trifluoromethyl)phenyl]ureido}phenoxy)-A/ 2 -methylpyridine-2-carboxamide
(Compound I — sorafenib)

1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-hydroxyphenyl)urea (35 g, 0.1060 mol) was
20 dissolved in dry N,N-dimethyl formamide (100 ml) and potassium tert-butoxide (14.28 g,
0.1272 mol) was added in one lot at room temperature. The reaction mass was stirred at
ambient temperature for 2-3 hours and 4-chloro-N-methyl picolinamide (18.09 g, 0.1060
mol) was added in one lot. The reaction mass was maintained at 60-70°C for 2-3 hours
and cooled to room temperature. It was then diluted with ethyl acetate and the organic
25 layer was washed with water followed by 1N HCI and finally with brine. The organic layer
was separated, dried over sodium sulfate and degassed to obtain solid. The obtained solid
was stripped with ethyl acetate, finally slurried in acetonitrile (350 ml) at room temperature,
filtered and vacuum dried to give 4-(4-{3-[4-Chloro-3-

(trifluoromethyl)phenyl]ureido}phenoxy)-A/ 2 -methylpyridine-2-carboxamide (sorafenib) (32
30 g).

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Example 12: Synthesis of Sorafenib Tosylate (Compound VII)

4-(4-{3-[4-chloro-3-(trifluoromethyl)pheny^

carboxamide (sorafenib) (50 g, 0.1075 mol) was suspended in acetone (500 ml) at
5 ambient temperature, p-toluene sulfonic acid (25 g, 0.1398 mol) was dissolved in acetone
(250 ml) and this solution was charged to above reaction mass drop wise in 15 minutes
and the obtained precipitate was stirred for 1-2 hours at ambient temperature, filtered and
washed with acetone (100 ml). It was then vacuum dried for 12 hours at 50°C to afford 4-
4-(4-{3-[4-Chloro«3-(trifluoromethyl)phenyl]ureido}phenoxy)-A^-methylpyridine-2-
10 carboxamide tosylate (sorafenib tosylate) (65 g).

Example 13: Synthesis of N-methyl-4-(4-ureidophenoxy)picolinamide (Compound 6)

A solution of sodium cyanate (5.5 g, 0.0846 mol) in water (55 ml) was prepared. This clear
15 solution was then added to the stirred solution of 4-(4-aminophenoxy)-N-
methylpicolinamide hydrochloride (V) (25 g, 0.0894 mol) in water (125 ml) drop wise
maintaining ambient temperature of the reaction mass. The reaction mass was then stirred
for 24 hours at the same temperature and the obtained solid was then filtered, washed
thoroughly with water and vacuum dried at 80°C to obtain (16 g) of the N-methyl-4-(4-
20 ureidophenoxy)picolinamide .

Example 14: Synthesis of Sorafenib

N-methyl-4-(4-ureidophenoxy)picolinamide (50 g, 0.1746 mol), 1,8-
25 diazabicyclo[5.4.0]undec-7-ene (33.95 ml, 0.2270 mol) and 3-trifluoromethyl-4-
chloroaniline (34.2 g, 0.1746 mol) were mixed with N,N-dimethyl formamide (200 ml)
(DMF) and the reaction mass was heated to reflux for 24 hours. It was then cooled to room
temperature and quenched in water (600 ml). The quenched mass was extracted
repeatedly with ethyl acetate and the combined ethyl acetate layer was then back washed
30 with water to remove DMF traces. It was then dried over sodium sulfate and evaporated

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under vacuum to obtain solid. The solid thus obtained was then slurried in ethyl acetate
(400 ml) at ambient temperature and filtered to give 4-(4-(3-(4-chloro-3-
(trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinamide (sorafenib base) (64 g).

5 Example 15: Synthesis of phenyl 4-(2-(methylcarbamoyl)pyridin-4-
yloxy)phenylcarbamate (Compound 7)

4-(4-aminophenoxy)-N-methylpicolinamide (35 g, 0.1440 mol) was dissolved in
dichloromethane (350 ml) and pyridine (64 ml) was added to the reaction mass at ambient

10 temperature. The reaction mass was then cooled to 0°C to -5°C and a solution of phenyl
chloroformate (23.5 ml, 0.180 mol) in dichloromethane (125 ml) was added drop wise
maintaining the temperature of the reaction mass below 0°C. The reaction was stirred at
0°C to 5°C for 1-2 hours and quenched with water (200 ml) below 10°C. The organic
phase was separated, washed with water followed by 1N HCI (100 ml) and dried over

15 sodium sulfate and then concentrated to obtain solid. This solid was agitated with hexane
(350 ml) at ambient temperature for 2-3 hours and filtered. The obtained product was
vacuum dried at 50°C to give 4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenylcarbamate (48
g) as pale yellow solid.

20 Example 16: Synthesis of Sorafenib

A mixture of 4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenylcarbamate (25 g, 0.06871 mol)
and 3-trifluoromethyl-4-chloroaniline (13.4 g, 0.06871 mol) in acetonitrile (250 ml) was
refluxed for 24 hours when product precipitated out of reaction mass. The reaction mass
25 was cooled to room temperature and obtained product was filtered, washed with
acetonitrile till a clear filtrate was obtained. It was then vacuum dried to obtain 4-(4-(3-(4-
chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinamide (sorafenib base)
(28 g)

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Example 17: Synthesis of N-methyl-4-(4-(2,2,2-

trichloroacetamido)phenoxy)picolinamide (Compound 8)

The clear solution of 4-(4-aminophenoxy)-N-methylpicolinamide (100 g, 0.411 mol) in
5 dichloromethane (100 ml) was cooled to 0°C to -5°C and pyridine (83 ml, 1.02 mol) was
added in one lot to the reaction mass. It was then agitated at same temperature for 15
minutes and a solution of trichloroacetyl chloride (60 ml, 0.535 mol) in dichloromethane
(500 ml) was added dropwise maintaining temperature of the reaction mass below 0°C.
The reaction mass was then stirred for 2-3 hours below 0°C and quenched with water (500
10 ml) below 5°C. The organic phase was then separated and aqueous layer was reextracted
with dichloromethane. The combined dichloromethane layer was washed with water, dried
over sodium sulfate and evaporated under vacuum to obtain (72 g) of the desired product.

Example 18: Synthesis of N-methyl-4-(4-(2,2,2-

15 trichloroacetamido)phenoxy)picolinamide (Compound 8)

The clear solution of 4-(4-aminophenoxy)-N-methylpicolinamide (100 g, 0.411 mol) in
dichloromethane (100 ml) was cooled to 0°C to -5°C and pyridine (83 ml, 1.02 mol) was
added in one lot to the reaction mass. It was then agitated at same temperature for 15

20 minutes and a solution of trichloroacid anhydride (98 ml, 0.535 mol) in dichloromethane
(500 ml) was added dropwise maintaining temperature of the reaction mass below 0°C.
The reaction mass was then stirred for 2-3 hours below 0°C and quenched with water (500
ml) below 5°C. The organic phase was then separated and aqueous layer was re-
extracted with dichloromethane. The combined dichloromethane layer was washed with

25 water, dried over sodium sulfate and evaporated under vacuum to obtain (70 g) of the
desired product.

Example 19: Synthesis of

trichloroacetamido)phenoxy)picolinamide (Compound 8)

30

N-methyl-4-(4-(2,2,2

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4-(4-aminophenoxy)-N-methylpicolinamide (35 g, 0.144 mol ) was mixed with ethyl-2,2,2-
trichloroacetate (50 ml, 0.27 mol) in toluene (350 ml) at ambient temperature . The mixture
was then heated to 100°C under distillation mode for 2-3 hours. The organic solvent was
degassed under reduced pressure to obtain oil. This oil was triturated with hexane (500
5 ml) to obtain (49 g) of the desired solid.

Example 20: Synthesis of Sorafenib

N-methyl-4-(4-(2,2,2-trichlorochloroacetamido)phenoxy)picolinamide (25 g, 0.0644 mol)
10 was dissolved in N,N-dimethyl formamide (75 ml). 1,8-Diazabicyclo[5.4.0]undec-7-ene
(11.35 ml, 0.0805 mol) and 3-trifluoromethyl-4-chloroaniline (12.60 g, 0.0644 mol) were
added in one lot. The reaction mass was then heated to 110°C for 8-9 hours, cooled to
room temperature and quenched in water (250 ml). The quenched mass was extracted
repeatedly with ethyl acetate and the combined ethyl acetate layer was back washed with
15 water to remove DMF traces. It was dried over sodium sulfate and evaporated under
vacuum to obtain solid. The obtained solid was slurried in ethyl acetate (350 ml) at
ambient temperature and filtered to give 4-(4-(3-(4-chloro-3-
(trifluoromethyI)phenyl)ureido)phenoxy)-N-methylpicolinamide (sorafenib base ) (20 g).

20 Example 21: Synthesis of phenyl 4-chloro-3-(trifluoromethyl)phenylcarbamate
(Compound 2)

3-trifluoromethyl-4-chloroaniline (55 g, 0.281 mol) and pyridine (56 ml, 0.7030 mol) were
dissolved in dichloromethane (550 ml). The reaction mass was cooled to 0°C to -5°C and

25 a solution of phenyl chloroformate (46 ml, 0.3515 mol) in dichloromethane (200 ml) was
added drop wise maintaining the temperature of the reaction mass below 0°C. The
reaction mass was stirred at 0°C to 5°C for 1-2 hours and quenched with water (250 ml)
below 10°C. The organic phase was separated and washed with water followed by 1N HCI
(100 ml). It was dried over sodium sulfate and concentrated to obtain solid. This solid was

30 agitated with hexane (500 ml) at ambient temperature for 2-3 hours and filtered. The

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obtained product was the vacuum dried at 50°C to give phenyl 4-chloro-3-
(trifluoromethyl)phenylcarbamate (85 g) as white solid.

Example 22: Synthesis of Sorafenib

5

Phenyl 4-chloro-3-(trifluoromethyl)phenylcarbamate (100 g, 0.3174 mol) and 4-(4-
aminophenoxy)-N-methylpicolinamide (77.14 g, 0.3174 mol) were dissolved in N,N-
dimethyl formamide (300 ml) to obtain a clear reaction mass. The reaction mass was
agitated at 40-45°C for 2-3 hours, cooled to room temperature and diluted with ethyl

10 acetate (1000 ml). The organic layer was washed with water (250 ml) followed by 1N HCI
(250ml) and finally with brine (250 ml). The organic layer was separated, dried over
sodium sulfate and degassed to obtain solid. This solid was stripped with ethyl acetate and
finally slurried in ethyl acetate (1000 ml) at room temperature. It was then filtered and
vacuum dried to give (118 g) of 4-(4-(3-(4-chloro-3-

15 (trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinamide (sorafenib base).

Example 23: Synthesis of 1-(4-chloro-3-(trifluoromethyl)phenyl)urea (Compound 4)

Sodium cyanate (1.7 g, 0.02mol) was dissolved in water (17ml) at room temperature to
20 obtain a clear solution. This solution was then charged drop wise to the clear solution of 3-
trifluoromethyl-4-chloroaniline (5 g, 0.025 mol) in acetic acid (25 ml) at 40°C-45°C within 1-
2 hours. The reaction mass was agitated for whole day and cooled gradually to room
temperature. The obtained solid was filtered washed with water and vacuum dried at 50°C
to afford the desired product (5.8 g) i.e. 1-(4-chloro-3-(trifluoromethyl)phenyl)urea.

25

Example 24: Synthesis of Sorafenib

1-(4-chloro-3-(trifluoromethyl) phenyl)urea (15 g, 0.0628 mol), 1,8-
diazabicyclo[5.4.0]undec-7-ene (11.75 ml, 0.078 mol) and 4-(4-aminophenoxy)-N-
30 methylpicolinamide (15.27 g,0.0628 mol) were mixed with dimethyl sulfoxide (45 ml) and

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the reaction mass was then heated to 110-120°C for 12-18 hours. The reaction mass was
cooled to room temperature and quenched in water (250 ml). The quenched mass was
extracted repeatedly with ethyl acetate and the combined ethyl acetate layer was then
back washed with water. It was dried over sodium sulfate and evaporated under vacuum
5 to obtain solid. The obtained solid was slurried in acetonitrile (150 ml) at ambient
temperature and filtered to give 4-(4-(3-(4-chloro-3-(trifluoromethyl) phenyl) ureido)
phenoxy)-N-methylpicolinamide (sorafenib base) (17.5 g).

Example 25: Synthesis of 2,2,2-trichloro-N-(4-chloro-3-(trifluoromethyl) phenyl)
10 acetamide. (Compound 3)

The clear solution of 3-trifluoromethyl-4-chloroaniline (45 g, 0.230 mol) and pyridine (37
ml, 0.460 mol) in dichloromethane (450 ml) cooled at 0°C to -5°C and a solution of
trichloroacetyl chloride (31 ml, 0.2876 mol) in dichloromethane (100 ml) was added drop

15 wise maintaining temperature of the reaction mass below 0°C. The reaction mass was
then stirred for 1 hour below 0°C and quenched with water (250 ml) below 5°C. The
organic phase was separated and aqueous layer was re-extracted with dichloromethane.
The combined dichloromethane layer was washed with water, dried over sodium sulfate
and evaporated under vacuum to obtain (62 g) of the desired product i.e. 2,2,2-trichloro-N-

20 (4-chloro-3-(trifluoromethyl) phenyl) acetamide.

Example 26: Synthesis of 2,2,2-trichloro-N-(4-chloro-3-(trifluoromethyl) phenyl)
acetamide. (Compound 3)

25 The clear solution of 3-trifluoromethyl-4-chloroaniline (45 g, 0.230 mol) and pyridine (37
ml, 0.460 mol) in dichloromethane (450 ml) cooled at 0°C to -5°C and a solution of
trichloroacid anhydride (54.85 ml, 0.299 mol) in dichloromethane ( 100 ml) was added drop
wise maintaining temperature of the reaction mass below 0°C. The reaction mass was
then stirred for 1 hour below 0°C and quenched with water (250 ml) below 5°C. The

30 organic phase was separated and aqueous layer was re-extracted with dichloromethane.

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The combined dichloromethane layer was washed with water, dried over sodium sulfate
and evaporated under vacuum to obtain (60 g) of the desired product i.e. 2,2,2-trichloro-N-
(4-chloro-3-(trifluoromethyl) phenyl) acetamide.

5 Example 27: Synthesis of 2,2,2-trichloro-N-(4-chloro-3-(trifluoromethyl) phenyl)
acetamide. (Compound 3)

3-trifluoromethyl-4-chloroaniline (60 g, 0.3067 mol) with ethyl-2,2,2-trichloro acetate (120
ml, 0.6134 mol ) were mixed in toluene (600 ml) at room temperature. The mixture was
10 then refluxed for 2-3 hours. The organic solvent was degassed under reduced pressure to
obtain oil. This oil was stirred with hexane (1000 ml) to obtain 2,2,2-trichloro-N-(4-chloro-3-
(trifluoromethyl)phenyl)acetamide (100 g).

Example 28: Synthesis of Sorafenib

15

2,2,2-trichloro-N-(4-chloro-3-(trifluoromethyl)phenyl)acetamide (45 g, 0.1319 mol) was
refluxed in N,N-dimethyl formamide (100 ml) with 1,8-diazabicyclo[5.4.0]undec-7-ene
(24.67 ml, 0.1649 mol) and 4-(4-aminophenoxy)-N-methylpicolinamide (32.07 g, 0.1319
mol) for 24 hours and cooled to room temperature. The reaction mass was quenched in

20 water (1000 ml). The quenched mass was extracted repeatedly with ethyl acetate and the
combined ethyl acetate layer was then back washed with water to remove DMF traces. It
was dried over sodium sulfate and evaporated under vacuum to obtain solid. The obtained
solid was slurried in ethyl acetate (1000 ml) at ambient temperature and filtered to give 4-
(4-(3-(4-chloro-3-(trifluoromethyl) phenyl) ureido)phenoxy)-N-methylpicolinamide

25 (sorafenib base) (52 g).

Example 29: Synthesis of 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-hydroxyurea
(Compound 9)

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Ethyl 4-chloro-3-(trifluoromethyl)phenylcarbamate (10 g, 0.0373 mol) and hydroxyl amine
hydrochloride (13 g, 0.1868 mol) were refluxed in acetic acid for 12 hours and the organic
layer was evaporated under vacuum to get oil. This oil was mixed with water (100 ml) and
the obtained precipitate was stirred at room temperature for 1-2 hours. The obtained solid
5 was filtered and washed thoroughly with water. The wet cake was vacuum dried at 50°C to
afford 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-hydroxyurea (6.8 g) as a white crystalline
solid.

Example 30: Synthesis of Sorafenib

10

1-(4-chloro-3-(trifluoromethyl)phenyl)-3-hydroxyurea (5 g, 0.0196 mol) was suspended in
N,N-dimethyl formamide (15 ml) with triethyl amine (8.2 ml, 0,0589 mol) and 4-(4-
aminophenoxy)-N-methylpicolinamide (4.7 g, 0.0196 mol). The reaction mass was then
heated to 125°C for 4 days. The reaction mass was concentrated under reduced pressure

15 and the obtained residue was quenched with water (50 ml) at room temperature. The
aqueous layer was extracted repeatedly with ethyl acetate and the combined ethyl acetate
layer was back washed with water. Degassing of the ethyl acetate gave semisolid which
upon agitation in acetonitrile (50 ml) at ambient temperature for 2-3 hours gave desired
product. The product was filtered and vacuum dried to obtain 4-(4-(3-(4-chloro-3-

20 (trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinamide (sorafenib base) ( 2.5 g).

Example 31 : Synthesis of Sorafenib Tosylate

4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinamide
25 (sorafenib base) (100 g, 0.2152 mol) was suspended in acetone ( 1000 ml) at ambient
temperature, p-toluene sulfonic acid (50 g, 0.290 mol ) was dissolved in acetone (500 ml)
and this solution was charged to above reaction mass drop wise in 15 minutes. The
obtained precipitate was stirred for 1-2 hours at ambient temperature, filtered and washed
with acetone (500 ml). It was vacuum dried for 12 hours at 50°C to afford 4-(4-(3-(4-chloro-

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3-(trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinamide tosylate (Sorafenib
Tosylate)(130g)

It will be appreciated that the invention may be modified within the scope of the appended
5 claims.

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CLAIMS

1 . A compound of formula (A)

59

wherein R' is selected from the group consisting of -C(0)OA, -C(0)CX 3 , -C(0)NH 2 ,-C(0)-

NHOH or

an

10 2. A compound according to claim 1, having formula (2)

OF

ci

o
U

H I

Carbamate derivative
(2)

wherein A is alkyl or aryl.

3. A process for preparing carbamate derivative (2) comprising reacting 3-
15 trifluoromethyl-4-chloroaniline with a haloformate (2a) or a carbonate derivative (2b) in the
presence of a base and a solvent

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CF

CI

O

x

2a

CI

NH

3- irifluororrieth\l-

4- chloro aniline

on ©

■A

2b

o
U

H A

Carbamate derivative
(2)

wherein in haloformate (2a), A is alkyl or aryl, , and in carbonate (2b), A is alkyl, aryl or the
two A groups taken together form a 5 to 7 membered ring.

4. A compound according to claim 1, having formula (3)

Anilide derivative (3)

wherein X is halogen.

10

5. A process for preparing anilide derivative (3) comprising reacting 3-trifluoromethyl-
4-chloroaniline with a trihaloalkyl halide, a trihaloalkyl anhydride or a trihaloalkyl ester to
obtain anilide derivative (3)

o

x

x cx~

OR 3
(CX3CO) 2 0 OR
CX3COOR

NH

3-trifluoromethyl-4-
chloroaniline

Trihaloalkyl halide
or anhydride or ester

15

wherein X is halogen and R is alkyl group.

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A compound according to claim 1, having formula (4)

Urea derivative (4)

7. A process for preparing urea derivative (4) comprising reacting 3-trifluoromethyl-4-
chloroaniline with an alkali cyanate in the presence of an acid to obtain urea derivative (4)

MOCN ci

o

I j

3-trifluonomethy1-4-chioro

aniline |>ea derivative (4)

10

wherein M is an alkali metal.

8. A compound according to claim 1, having formula (1)

H H

15

9. A process for preparing a compound of formula (1) comprising reacting carbamate
derivative (2) with 4-aminophenol in the presence of a solvent

20

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62

(2)

wherein A is alkyl or aryl.

10. A process according to claim 9, wherein the carbamate derivative (2) is prepared
5 according to claim 3.

11. A process for preparing a compound of formula (1) comprising reacting anilide
derivative (3) with 4-aminophenol in a solvent to obtain compound (1)

wherein X is halogen.

12. A process according to claim 11, wherein the anilide derivative (3) is prepared
according to claim 5.

15

13. A process for preparing a compound of formula (1) comprising reacting urea
derivative (4) with 4-aminophenol in a solvent to obtain compound (1).

CF,

CI

HO

O

x

N NH,
H

Urea derivative (4)

OH

4-aminophenol

N N
H H

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14. A process according to claim 13, wherein the urea derivative (4) is prepared
according to claim 7.

5 15. A process for preparing a compound of formula (1) comprising reacting phenoxy
urea (5) with 3-trifluoromethyl-4-chloroaniline in a solvent in the presence of a base to
obtain compound (1).

CF,

HO

a

Phenaxy Lrea (5)

NH,

CI

3- iriflu orom ethyl- 4- chlo ro
aniline

CF.

H H 1 J

10

16. A process according to claim 15, wherein the phenoxy urea (5) is prepared by
reacting 4-aminophenol with an alkali cyanate in the presence of an acid to obtain
phenoxy urea (5)

HO-

HO

NH

MOCN

N
H

O

x

NH

4-aminophenol

Phenoxy urea (5)

15 wherein M is an alkali metal.

17. A compound of formula (6)

G

NH

L6j

20

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18. A process for preparing a compound of formula (6) comprising reacting 4-(4-
aminophenoxy)-N-methylpicolinamide or a salt thereof with an alkali cyanate in the
presence of a protic solvent to obtain compound (6)

MOCN

jsj u " 1 £f

5

4-(4-aminophenoxy)- N-
methiylpicoliramicte [V)

wherein M is an alkali metal.

(6]

19. A compound of formula (7)

10

wherein A is alkyl or aryl.

20. A process for preparing compound (7) comprising reacting 4-(4-aminophenoxy)-N-
15 methylpicolinamide or a salt thereof with a haloformate or a carbonate derivative in the
presence of a base to obtain compound (7)

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2a 2b

I

4-{4-aminopheno)cy)-N- ■ ^

methyl pi colinamide (V) v ^r^-^"*'^ , ^-r^

+ OR

A

0 ^ o

i

A

CD

wherein X is halogen and in haloformate (2a) A is alkyl or aryl, and in carbonate (2b), A is
alkyl, aryl or the two A groups taken together form a 5 to 7 membered ring.

5

21 . A compound of formula (8)

0

wherein X is halogen.

10

22. A process for preparing compound (8) comprising reacting 4-(4-aminophenoxy)-N-
methylpicolinamide or a salt thereof with a trihaloalkyl halide, a trihaloanhydride or a trihalo
ester to obtain intermediate (8)

o

OR

f ^^° -^>^w^ NH x cx 3 Q o

\J ' (CX3CO) 2 OOR Jl Jfj

CX3COOR OK^^Hn^^

4^{4^aminopheroxy)-N- *~

methyl pi coli rami de [V) Trihaloalkyl halide

-| g + or anhydride or ester 1£J

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wherein X is halogen and R is alkyl group.

23. A compound according to claim 1 , having formula (9)

CI

0

« A r„

24. A process for preparing hydroxyl urea derivative (9) comprising reacting carbamate
derivative (2) with a hydroxyl amine in a protic solvent

CF

CI

0

o

H

i

H T

A OH

Carbamate derivative

(2) m

10

wherein A is alkyl or aryl.

25. A process for preparing sorafenib or a salt thereof comprising the use of a
1 5 compound of formula (A)

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wherein R' is selected from the group consisting of hydrogen, -C(0)OA, -C(0)CX 3 , -

A

C(0)NH 2) -C(0)-NHOH or

5 26. A process according to claim 25, comprising reacting a compound of formula (1)
with 4-chloro-N-methyl-2-pyridine carboxamide in the presence of a base to obtain
sorafenib.

CF

CI

CI

+

CI

H H

4-chloro-N -methyl
-2-pyridine carboxamide

H H

NH
I

SQ RAPE NIB (|)

10

27. A process according to claim 26, wherein the compound of formula (1) has been
prepared according to any one of claims 9 to 16.

28. A process according to claim 25, comprising reacting compound (6) with 3-
15 trifluoromethyl-4-chloroaniline in the presence of a base and a solvent to obtain sorafenib.

aniline

(6} + SORAFENIB (|)

20 29. A process according to claim 28, wherein the compound of formula (6) has been
prepared according to claim 18.

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30. A process according to claim 25, wherein R' is hydrogen and the process comprises
reacting compound (7) with 3-trifluoromethyl-4-chloroaniline to obtain sorafenib

3-trifluoromethyt-4-chloro H H

aniline

+ SORAFENIB (|)

5 wherein A is alkyl or aryl.

31. A process according to claim 30, wherein compound (7) has been prepared
according to claim 20.

10 32. A process according to claim 25, wherein R' is hydrogen and the process comprises
reacting compound (8) with 3-trifluoromethyl-4-chloroaniline in the presence of a base to
obtain sorafenib

°T1

► >r^i d Nr^r^NH

Cx * H " 3-irifluorometh^4.chloro B B

aniline

GD , SORAFENIB (|)

15 wherein X is halogen.

33. A process according to claim 32, wherein compound (8) has been prepared
according to claim 22.

20 34. A process according to claim 25, wherein R' is -C(0)OA and the compound of
formula (A) is a carbamate derivative of formula (2)

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Gl

N
H

A

O

O

(2)

wherein A is alkyl or aryl, the process comprising condensing 4-(4-aminophenoxy)-N-
methylpicolinamide or a salt thereof with carbamate derivative (2) to obtain sorafenib.

5 35. A process according to claim 34, wherein compound (2) has been prepared
according to claim 3.

36. A process according to claim 25, wherein R' is -C(0)CX 3 and the compound of
formula (A) is an anilide derivative of formula (3)

wherein X is halogen, wherein the process comprises condensing 4-(4-aminophenoxy)-N-
methylpicolinamide or a salt thereof with anilide derivative (3) in the presence of a base to
15 obtain sorafenib.

37. A process according to claim 36, wherein compound (3) has been prepared
according to claim 5.

20 38. A process according to claim 25, wherein R' is -C(0)NH2 and the compound of
formula (A) is a urea derivative of formula (4)

10

GF

Anilide derivative (3)

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ci

N
H

N H

Oea derivative (4j

the process comprising condensing 4-(4-aminophenoxy)-N-methylpicolinamide or a salt
5 thereof with the urea derivative (4) in the presence of a base to obtain sorafenib.

39. A process according to claim 38, wherein the urea derivative (4) is prepared
according to claim 7.

10 40. A process according to claim 25, wherein R' is -C(0)-NHOH and the compound of
formula (A) is a hydroxy urea derivative (9)

and the process comprises by condensing 4-(4-aminophenoxy)-N-methylpicolinamide or a
salt thereof with hydroxy urea derivative (9) to obtain sorafenib.

41. A process according to claim 40, wherein compound (9) has been prepared
20 according to claim 24.

15

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42. A process according to any one of claims 25 to 41, wherein sorafenib is converted
to sorafenib tosylate.

5